Approximately 171,900 new cases of lung cancer are diagnosed annually.

Greater than 50% of patients present with regional disease (Stage IIIA or IIIB) which is generally treated with chemotherapy and radiation.

Overall survival continues to be poor even with the use of chemotherapy and 3D conformal radiation. Recent data from MD Anderson demonstrated a 2 year overall survival of 41% and a 5 year overall survival of 19%. These results are consistent with out studies.

In order to improve local control, more aggressive therapy is necessary. However, this is limited by treatment related toxicity, particularly pneumonitis.

Pneumonitis is the primary dose limiting toxicity for radiation and can also be worsened by concurrent chemotherapy.

Data from MD Anderson demonstrated that approximately 30% of patients treated with radiation for lung cancer will develop pneumonitis after 1 year.

Further studies from MD Anderson demonstrated that the risk of pneumonitis was related to the volume of lung exposed to low doses of radiation. This study found that no patients developed pneumonitis if their V5 was less than 42%.

Pneumonitis can be progressive, irreversible, and debilitating.

Currently there is a paucity of treatments for pneumonitis.

Clinical and histological manifestations of pneumonitis and the potential mechanisms of action.

Pneumonitis first appears as consolidation radiologically. This can advance to fibrosis which can progressively worsen.

Histologically specimens from patients with pneumonitis demonstrate increased secretions within the alveoli followed by fibrosis.

There are several theories as to how pneumonitis occurs.

It is thought that radiation or chemotherapy, such as bleomycin, can increase oxidative damage initiating a cascade of events. This results in increased release of inflammatory cytokins, which are thought to initiate an inflammatory process. Prior studies have demonstrated that IL-1 and IL-6 may play an important role in this cascade (Chen Y. Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):260-6) . This study found that in patients who developed pneumonitis there tended to be a higher baseline level of IL-6 and after radiation there was a surge of IL-6.

The arachidonic acid (AA) pathway has been shown to play an important role in the development of pneumonitis. AA can be metabolized by a number of enzymes, including cycloxygenases, lipoxygenase, and cytochrome p450. AA metabolism can lead to the formation of a variety signaling molecules some of which have been shown to play a role in inflammation as well as tumor growth. Alternatively, other metabolites have been shown to have an anti-tumoral or anti-inflammatory effect. It is thought that an imbalance between the pro and anti-inflammatory effects, i.e. and imbalance between the yin and the yang of the inflammatory equilibrium may lead to pneumonitis.

Ku Mai Cai (Ixeris Chinensis) is an herb that is used in traditional Chinese medicine. It is the main component of Fei Tai, a traditional blend of Chinese herbs thought to lead to a long life. Ku Mai Cai is thought to have the potential to treat and prevent pneumonitis. Additionally, it is thought that Ku Mai Cai may have anti-tumoral effects.

Ku Mai Cai has been used in Chinese medicine for thousands of years. It is traditionally used to treat inflammation and is used topically to treat “growths.”

There have been several studies investigating the active ingredients in Ku Mai Cai. The flavonoids appear to play an important role in Ku Mai Kai's effectives. Flavonoids have been shown to have anti-inflammatory and anti-tumoral effects.

Prior studies from China have shown that derivative of Ku Mai Cai could reduce bleomycin induced lung fibrosis in mice. This appeared to be due to a reduction in the expression of inflammatory cytokins.

Preliminary studies in mice performed at MD Anderson demonstrated that Ku Mai Cai was able to reduce edema in the ears of mice. There was a reduction in the expression of inflammatory cytokins, but this difference was not statistically significant.

Experiments in human lung cancer cell lines were also performed at MD Anderson. Ku Mai Cai appeared to increase the expression of anti-tumoral cytokins and inhibited tumor cell growth.

Clinical studies from China found that patients with SARS treated with Fei Tai had a better quality of life. This study suggests that Fei Tai is non-toxic.

There has been an attempt by MD Anderson to start a large clinical trial using Ku Mai Cai for the treatment and prevention of pneumonitis, but it has failed to generate a large amount of interest. Currently smaller trials are underway at MD Anderson.

Author's Conclusions

Local/regional control remains a large problem in patients with locally advanced lung cancer.

Dose escalation to improve local control is limited by pneumonitis.

The treatments available to treat pneumonitis are limited.

The traditional Chinese concept of yin and yang can be used to explain the balance between inflammatory and anti-inflammatory cytokines. Disturbances in this balance may lead to pneumonitis.

Preclinical and clinical studies suggest that Ku Mai Cai may be beneficial in the treatment of pneumonitis.

Ku Mai Cai still has a long way to go prior to being accepted for use in the US .

Clinical/Scientific Implications

The use of Ku Mai Cai as a therapeutic is in its infancy. Further studies of effective in vivo dose, such as a phase I study to determine if there are dose limiting toxicities are necessary prior to a phase II or phase III study being initiated. Furthermore, Ku Mai Cai likely has multiple active compounds and further studies to define which one, or combination or compounds causes its effects would be of interest. Use of these compounds alone could limit toxicity. Further clinical and preclinical evidence are required prior to the wide spread clinical study of Ku Mai Cai.